Therapeutic Advances in Medical Oncology最新文献

Background: Regorafenib targets tumor angiogenesis and oncogenic signaling by inhibiting multiple kinases involved in angiogenesis, oncogenesis, and the tumor microenvironment. Chemotherapy of FOLFIRI causes direct cytotoxic damage to tumor cells.

Objectives: We evaluated the efficacy and safety of regorafenib plus FOLFIRI with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping-guided irinotecan dose escalation in patients with metastatic colorectal cancer (mCRC) who had received second- or third-line systemic therapy.

Design: A total of 153 patients were randomized (at a ratio of 2:1) to receive either regorafenib plus FOLFIRI (experimental group, 102 patients) or regorafenib alone (control group, 51 patients).

Methods: Both groups received regorafenib (120 mg daily) for 21 consecutive days in 28-day cycles. In addition, the experimental group received FOLFIRI with UGT1A1 genotyping-guided irinotecan dose escalation. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), disease control rate (DCR), and adverse events.

Results: The final cohort included 116 patients. The experimental group exhibited significant improvement in PFS (p = 0.016) but marginally significant improvements in DCR (p = 0.055). Specifically, PFS improved significantly for experimental group patients carrying wild-type rat sarcoma virus (RAS; p = 0.003) and those carrying left-sided colon tumors (p = 0.015). A trend toward improved OS was noted in experimental group patients carrying wild-type RAS (p = 0.096). No significant between-group difference was observed in the incidence of severe adverse events (all p > 0.05).

Conclusion: Our findings suggest that regorafenib plus FOLFIRI significantly improved PFS in patients with mCRC and offers a safety profile similar to that of regorafenib alone. This regimen may be particularly beneficial for patients with mCRC carrying wild-type RAS and those carrying left-sided tumors. However, larger phase III randomized controlled trials are necessary to confirm the efficacy and safety of this combination therapy before adoption into standard practice.

Trial registration: ClinicalTrials.gov registry: NCT03880877 (https://clinicaltrials.gov/search?cond=NCT03880877).

Background: Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are classical tumor markers in clinical practice. However, the relationship between tumor markers and prognosis in hepatocellular carcinoma (HCC) patients receiving immune checkpoint inhibitor (ICI) therapy remains unclear.

Objectives: This study aims to explore the prognostic value of AFP and PIVKA-II in HCC patients treated with ICIs.

Design: This study was a single-center, retrospective investigation aimed to assess the prognostic value of AFP and PIVKA-II in HCC patients receiving immune checkpoint inhibitors.

Methods: This retrospective study included HCC patients who received ICIs treatment at Wuhan Union Hospital between July 2020 and March 2024. Serum AFP and PIVKA-II levels were collected before treatment. Patients were stratified into two groups based on AFP ⩾ 400 μg/L (yes = 1, no = 0) and PIVKA-II ⩾ 40 mAU/mL (yes = 1, no = 0). A total of 61% (114/186) of patients scored ⩽ 1, while 39% (72/186) scored 2. The objective response rate (ORR) and disease control rate (DCR) were calculated for both groups. Kaplan-Meier survival curves and Cox regression models were used to analyze overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic curves were generated to demonstrate the predictive ability of combined independent prognostic factors for long-term survival.

Results: The cohort consisted of 186 patients, divided into the low-risk group (n = 114) and the high-risk group (n = 72). Among all patients, 34.4% (64/186) achieved complete or partial response. Concurrent elevation of AFP and PIVKA-II was inversely associated with ORR (p = 0.012). The high-risk group exhibited significantly shorter OS (adjusted HR: 2.226 (95% CI: 1.410-3.513); p < 0.001) compared to the low-risk group. The integrated model combining AFP, PIVKA-II, and Barcelona Clinic liver cancer stage demonstrated moderate to good predictive capability for long-term risk stratification, with time-dependent area under the curves of 0.78 (9-month), 0.68 (12-month), and 0.63 (15-month).

Conclusion: Concurrent elevation of AFP and PIVKA-II is significantly associated with shorter survival outcomes in HCC patients following ICI therapy.

Background: Liver metastases (LM) in advanced non-small-cell lung cancer (NSCLC) are associated with poor clinical outcomes. The tolerogenic immune microenvironment in the liver may contribute to inferior response to immune checkpoint inhibitors (ICIs). We hypothesized that the presence of LM may be associated with an expanded peripheral myeloid population, using the neutrophil-to-lymphocyte ratio (NLR) as a surrogate in patients treated with ICIs.

Objectives: We evaluated the impact of LM and NLR on clinical outcomes in patients with advanced NSCLC treated with ICIs.

Design: This was a retrospective analysis conducted at a single cancer center.

Methods: We reviewed the records of 324 patients with advanced NSCLC treated with programmed death ligand-1 (PD-L1) inhibitors as monotherapy or in combination with cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated among patients with and without LM in NLR-High (NLR ⩾ 5) and NLR-Low (NLR < 5) subgroups.

Results: Patients with LM had significantly higher median NLR compared to patients without LM (median 7.3 vs 4.5, p < 0.001). Patients with LM had significantly shorter median PFS (HR 1.54, p = 0.006) and median OS (HR 1.56, p = 0.014). Patients with LM who were NLR-High (LM+ NLR-H) had shorter median PFS and median OS (2.0 months and 5.4 months, respectively) compared to patients who had LM and were NLR-Low (LM+ NLR-L, median PFS 4.0 months and median OS 13.3 months). This trend was also observed within the PD-L1 > 50% subgroup. In 42 patients with evaluable response and LM, 25/42 (59.5%) of patients had concordant responses in the liver and extra-hepatic sites.

Conclusion: Patients with LM who are NLR-High had the poorest clinical outcomes to ICI, and this appeared to be irrespective of PD-L1 status. Ongoing translational work will provide further insight into tumor myeloid subpopulations that may correlate with treatment resistance.

Solitary fibrous tumours (SFT) are fibroblastic mesenchymal tumours that can develop virtually at any site. It usually affects adults, and its incidence is estimated as 1 new case per million people per year. SFT is characterized by a gene fusion involving NAB2 (NGFI-A-binding protein 2) and STAT6 (signal transducer and activator of transcription 6); a higher nuclear STAT6 immunostaining can be seen in SFT cells, and it is considered an excellent marker for immunohistochemical diagnosis. The 2020 WHO classification defines two categories for SFT: intermediate (rarely metastasizing) and malignant. Many risk stratification models have been proposed to predict the behaviour of these tumour identities. In case of localized SFTs, the cornerstone of the treatment remains surgery with the aim of negative margins (R0) when technically feasible. In intermediate/high-risk SFTs with positive margins (R1/R2) with no possibility to re-resection or in meningeal high-risk SFTs, adjuvant radiotherapy (RT) could be performed. Neoadjuvant RT could also have a role in both extra-meningeal and meningeal localizations. Sole RT could have a role in managing non-resectable SFTs even in a curative intent. Medical therapy plays an important role in the metastatic/advanced SFTs. Conventional chemotherapy may be used, with doxorubicin and dacarbazine being active though yielding poor responses. Other active drugs with currently ongoing studies in SFT are eribulin and trabectedin. Antiangiogenetic treatments have also been shown to provide benefit in this histological subtype. An area of recent investigation is immunotherapy, with an ongoing randomized trial comparing nivolumab + ipilimumab versus pazopanib in advanced rare soft tissue sarcomas, including SFTs. Despite its rarity and therefore the difficulty in performing prospective randomized trials with a large number of patients, many promising results in perioperative (radiotherapy) or in the metastatic (medical therapy) setting have been obtained. This review overviews the main characteristics and provides the current knowledge on standard therapies.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths in Germany. National data on the management of HCC remain scarce.

Objectives: This study aims to provide an up-to-date overview of clinical characteristics, treatment modalities, and survival outcomes among patients with HCC in Germany.

Design: This is a real-world retrospective study using health insurance data from BARMER.

Methods: Patients with an HCC diagnosis between 2016 and 2020 were identified in the BARMER database. Comorbidities, anticancer therapies, and treatment pathways of those patients were evaluated using descriptive statistics and survival analysis.

Results: A total of 2778 patients with HCC were identified. Of these, 1569 (56.5%) received any anticancer therapy. Transarterial chemoembolization (TACE; 22.3%), liver resection (LR; 20.9%), and systemic therapy (18.9%) were the most frequently used approaches. Survival varied significantly, with liver transplantation (LTx) offering the best outcomes, with a 5-year survival rate of 76%, followed by LR with 40%. Treatments with curative intent, including LTx, LR, and ablation, had a median survival of 40.4 months, compared to 9.7 months for non-curative modalities.

Conclusion: In Germany, a substantial proportion of HCC patients remain untreated. Therapies with curative intent, particularly transplantation, provide relevant survival benefits. Improving surveillance efforts could enhance the proportion of patients eligible for these modalities and may represent a critical step toward improved outcomes for patients with HCC.

Dedifferentiated ovarian carcinomas (DDOC) are rare and aggressive malignancies characterized by a mixture of differentiated and undifferentiated tumor components, often associated with poor prognosis. This case report describes a 55-year-old woman initially diagnosed with early-stage high-grade endometrioid ovarian carcinoma who experienced rapid disease progression during adjuvant platinum-based chemotherapy, culminating in death within 4 months. Retrospective molecular analyses revealed pathogenic variants in the SMARCA4 gene, leading to a revised diagnosis of DDOC. The tumor exhibited resistance to conventional chemotherapy, highlighting the challenges associated with managing this aggressive tumor subtype. In our case, molecular profiling identified two potentially targetable alterations: biallelic SMARCA4 loss and a pathogenic PIK3CA mutation, both of which may inform future therapeutic strategies. This case underscores the importance of integrating molecular diagnostics into routine practice for accurate classification and highlights the urgent need for personalized treatment strategies, including targeted and immunotherapy options, for this formidable tumor subtype.

Background: Hematoxylin and eosin (H&E) staining is routine in pathology but lacks cellular specificity. Multiplex immunofluorescence (mIF) captures spatial immune relationships in tumors, but cost and complexity limit clinical application. Novel approaches to yield similar information from readily available tumor histology are needed.

Objectives: Develop and validate a novel deep learning tool capable of translating standard H&E-stained histopathology images into high-fidelity synthetic mIF images that preserve immune cell information predictive of treatment response in breast cancer.

Design: Comparative model evaluation and predictive modeling in a retrospective breast cancer cohort.

Methods: Core-needle biopsies from 17 triple-negative breast cancer cases underwent mIF imaging. Hematoxylin and eosin and mIF images for DAPI (nuclei), pan-CK (tumor), CD3/CD4/CD8 (T-cells), and CD20 (B cells) were aligned. A pipeline outperforming standard Pix2Pix and CycleGAN image translation networks was developed, "multiplex Synthetic Immunofluoresence Generated through H&E Translation" (mSIGHT), which integrates a registration network to overcome misalignment between the input and target images. Generated images were evaluated with pixel-level metrics and biological metrics, including cell density and cell-to-cell adjacency. The pipeline was then applied to an external cohort to assess associations between predicted immune features and pathologic response to neoadjuvant chemotherapy.

Results: Generated images preserved immune cell distributions and proximity metrics correlated to the ground truth cell counts. In a cohort of 218 breast cancer cases treated with neoadjuvant chemotherapy, predicted density of CD8+ T cells was significantly associated with complete response (adjusted odds ratio 1.89, 95% confidence interval 1.23-2.80, p = 0.002), independent of receptor status, grade, and pathologist TIL annotations.

Conclusion: The mSIGHT pipeline enables translation of routine H&E slides into virtual mIF images with interpretable immune biomarkers, offering a scalable and affordable alternative to multiplex imaging. It also identifies immune features predictive of therapeutic response and has the potential to assist in the personalization of neoadjuvant therapy.

[This retracts the article DOI: 10.1177/1758835920982853.].

[This retracts the article DOI: 10.1177/1758835919875319.].

Background: Soft tissue sarcomas (STS) are rare, heterogeneous tumors with poor prognosis, often characterized by high recurrence rates and limited response to conventional chemotherapy in advanced stages. Vascular-targeting agents (VTA) have shown promising efficacy for STS in numerous clinical trials; however, the optimal agent and combination strategies remain undetermined.

Objectives: This work aims to compare the clinical efficacy and adverse events of different VTA-containing regimens for patients with STS.

Design: This study is a systematic review and network meta-analysis.

Data sources and methods: We searched PubMed, Embase, and the Cochrane Library for eligible randomized clinical trials. All trials with VTA as monotherapy or VTA-included regimens in the experimental or control groups were selected, except for some specific histological subtypes. Pooled hazard ratios (HRs) for survival data and odds ratios for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events with credible intervals were generated using R software. A Bayesian random-effects model was applied to rank different treatments based on the surface under the cumulative ranking curve (SUCRA) values.

Results: Seventeen articles covering 15 studies were included. Pairwise comparisons demonstrated prolonged progression-free survival (PFS) for tyrosine kinase inhibitor (TKI) versus placebo (HR 0.50, 95% confidence interval (CI) 0.32-0.83) and prolonged overall survival (OS) for monoclonal antibody plus chemotherapy versus placebo (HR 0.42, 95% CI 0.19-0.89). Vascular-disrupting agents (VDA) plus chemotherapy were ranked highest for OS (87.05%) and ORR (89.66%). TKI plus chemotherapy and TKI plus immunotherapy had higher SUCRA values for PFS (68.21%) and DCR (82.29%). TKI-based regimens were associated with higher incidences of hypertension, diarrhea, and elevated transaminase levels, whereas chemotherapy-based strategies resulted in higher incidences of hematological toxicity and constipation.

Conclusion: VTA-containing regimens showed promising activity and tolerability in patients with advanced STS. Combination regimens with TKI showed better efficacy for PFS and DCR. Novel VDA combined with chemotherapy showed potential to prolong OS and improve ORR.

Trial registration: PROSPERO website (registration number: CRD42024588134).